The overarching objective that has guided my research endeavors, collaborations and training opportunities has been to determine the mechanism by which sex hormones and neurosteroids interact with neurotransmitters to modulate behavior, mood and cognition in women. With my mentored K award, I have developed a unique program of clinical research that relies heavily on knowledge gained from molecular and basic neuroscience to inform our investigations of the pathogenesis of premenstrual dysphoric disorder (PMDD), postnatal depression (PPD) and perimenopausal mood and cognitive changes. To this end, I have employed proton magnetic resonance spectroscopy (1H-MRS) to obtain in vivo measures of amino acid neurotransmitter (AANt) concentrations under various hormonal conditions and pathologic states. Our 1H-MRS findings confirm that AANt levels are altered by changes in the neuroendocrine milieu. The research plan that I proposes herein will take full advantage of information obtained from our previous H-MRS studies to begin to tease apart the effects of individual neuroactive steroids on AANts and to inform our application of more dynamic MRS techniques to examine AANt synthesis and cycling in healthy menstruating women and those with PMDD. My aims during K02 funding are to (1) pursue studies of the biochemistry of AANt, (2) become proficient in MRS theory, data acquisition and analysis, (3) develop expertise in neurosteroid biosynthesis and measurement, and (4) advance my understanding of statistical models which are frequently applied to longitudinal samples (random effects). In addition, two projects are proposed (1) "The Impact of Fluoxetine Treatment on Neurosteroidogenesis and Cortical GABA and Glutamate Concentrations in Women with PMDD," funded by my recent R01 and (2) H-MRS and C-MRS Investigation of the Differential Effects of Estradiol, Progesterone and AIIopregnanolone on Cortical AANt Concentrations, Glutamate-Glutamine Cycling and GABA Synthesis in Women With &Without PMDD. As my K23 funding is drawing to an end (12/01/04), timely funding of this K02 grant will insure that I can focus on the career development plan and projects outlined herein. Without K02 funding, I will have to assume additional, non-research related activities. My translational research and educational endeavors over the past 4 years have insured that I am uniquely poised to advance our understanding of the neuroendocrine contribution to mood and behavior in women. With the full support of our Departments of Psychiatry and Obstetrics/Gynecology for my promotion to Associate Professor in July 2004, I am situated in an intellectually rich and supportive academic community that is certain to further my career development.